544P - Clinical and molecular features of primary central nervous system tumor with Lynch syndrome

Background

Central nervous system tumour (CNST) is a heterogeneous group of human tumors that vary significantly in incidence by age, sex, and race/ethnicity. Lynch syndrome (LS), caused by germline pathogenic variants (PVs) in mismatch repair (MMR) genes, leads to 2-8% lifetime risk to CNST. We aimed to identify clinical features of CNST with MMR PVs.

Methods

Germline mutations of MMR genes (including MLH1, MSH2, MSH6, PMS2) and microsatellite instability (MSI) were detected by next-generation sequencing (NGS) in CNST patients(pts). The pathogenicity of germline mutations was categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines.

Results

There were 47 of 4787 (0.98%) CNST pts identified with LS. The median age of LS CNST pts was 36 years (range: 3-77 years), and the detection rate of MMR PVs was higher in CNST pts< 40 years (n=28, p<0.05). Of 47 LS CNST included IDH-wildtype glioma (n=34, predominantly high-grade glioma), astrocytoma IDH-mutant(n=7), medulloblastoma(n=2), meningeal melanoma(n=1), pilocytic astrocytoma(n=1), diffuse hemispheric glioma H3 G34-mutant(n=1), ependymoma(n=1). This was the first report a pt with LS with meningeal melanoma. Unlike the conventional glioblastoma IDH-wildtype, LS-related high grade IDH-wildtype glioma did not have TERT promoter mutation, EGFR gene amplification, +7/−10 chromosome copy-number changes. In contrast, LS-associated high grade IDH-wildtype gliomas commonly harbor TP53, ATRX mutations. In addition, MSI-H was found in 31.9% (15/47) of LS CNST pts, MSI-L was found in 17.0% pts (8/47), and 51.1% (24/47) pts exhibited MSS.

Conclusions

MMR germline gene pathogenic mutations were carried by 1% of CNST pts, predominantly high-grade gliomas, and developed at an early age. Genetic profile of LS related high grade glioma was different from that of conventional GBMs, which suggested that the importance of adding MMR genes test to CNST.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.